In humans uric acid constitutes a strong antioxidant as well as the end product of purine metabolism. Lower blood uric acid is now emerging as a major molecular risk factor for idiopathic Parkinson's disease (PD). Moreover, our preliminary findings have demonstrated that plasma and CSF uric acid levels in early PD are highly significant predictors of a slower rate of PD progression based on clinical and neuroimaging measures in two large prospective clinical studies. These observations support a novel neuroprotective effect of uric acid or its determinants in PD, and prompted us to explore their role in an animal model of PD. The core hypothesis pursued by this proposal is that uric acid and its determinants confer protection against dopaminergic neuron degeneration in an animal model of PD. We will investigate the neuroprotective effects of uric acid and its precursor inosine in the mouse MPTP model of PD, using complementary genetic and pharmacological approaches to elevating uric acid (systemically or locally;acutely or chronically). The proposed work will define a prototypical interaction between an environmental neurotoxicant and a newly identified candidate neuroprotectant, which may be particularly amenable to therapeutic interventions. The proposed experiments stand to establish a biological basis for why uric acid predicts reduced risk and slower progression of the disease. Mechanistic insights from the project may substantiate novel yet realistic pharmacological strategies for preventing and slowing PD. PUBLIC HEALTH RELEVANCE The proposed research stands to elucidate neuroprotective effects of uric acid and its precursor inosine in a prototypic toxicant model of PD. The results of these studies may thus establish a biological basis for the inverse epidemiological and clinical associations between uric acid and PD, and provide a foundation for future mechanistic investigations. Together, the specific aims of this proposal seek to provide conceptually important and clinically relevant insights into the pathophysiology, the epidemiology and potentially the treatment of PD and related neurological disorders.